Engineering Solutions to Treat Inherited Blood Disorders

Due to the unwise choice to held the 59th ASH Annual Meeting in Atlanta this delicate time of the year and due to the possibly foreseeable and now prevailing harsh weather conditions Oncoletter as well as many other attendees of the meeting couldn't make it timely to reach Atlanta.

At this time Oncoletter can instead of a webcast only provide the abstracts of the following studies which were presented at the press conference this morning:

A correlation was observed between level of engraftment of gene-marked cells in peripheral blood and bone marrow and transfusion requirement. Preliminary data suggest that the applied clinical protocol for gene therapy with GLOBE LV is well tolerated and leads to significantly reduced transfusion requirement. Follow up analysis are ongoing and updated clinical outcome will be presented.

We have designed a panel of customized iPSCs reprogrammed from rare donors or genetically engineered to express rare blood group antigen phenotypes or combinations that are difficult or impossible to find as donor red cells. Any number of combinations not found in natural populations can be produced and generated in quantities sufficient for reagents. iRBC produced from these customized iPSCs can be used with standard blood bank assays and potentially provide the means to streamline and standardize antibody identification in alloimmunized patients with complex antibody specificities. In the future, when technology for scale-up is available, Rh null iRBCs could be used as “universal” donor cells for future therapeutic applications.

Based on preliminary results, treatment with GBT440 at 900 mg has been well tolerated in all 13 adolescents. Data from 4 adolescents at 12 weeks show a marked improvement in Hb and reduction in clinical measures of hemolysis. Importantly, hematologic improvements are seen in patients already maximally managed with hydroxyurea. TCD and PRO data suggest that TCD velocity (i.e. risk of stroke) and clinical symptoms may improve with GBT440 treatment. Overall, these results are consistent with in vivo inhibition of HbS polymerization by GBT440 and support the ongoing clinical evaluation of GBT440 as a potential disease-modifying therapy for SCD in an ongoing pivotal Phase 3 study.

In summary, gene therapy for newly diagnosed XSCID patients using a LV vector with targeted reduced exposure Bu conditioning is well tolerated and results in rapid T cell reconstitution in most cases. Efficient vector marking in bone marrow CD34+ cells, myeloid cells, and B cells indicate that this approach will likely provide broad immune reconstitution rather than restricted T cell correction seen in past trials using γ-retroviral vectors with no Bu.